Germline BRCA1 ‐Mutated Synchronous and Metachronous Pancreatic Acinar Cell Carcinoma With Long‐Term Survival

ABSTRACT Background Pancreatic acinar cell carcinoma (PACC) is a rare pancreatic neoplasm. Recently, molecular analysis revealed that PACC shows a high frequency of the BRCA1/2 mutation and is likely to be considered a cancer associated with hereditary breast and ovarian cancer (HBOC). Hereditary cancers, including HBOC, are characterized by multifocal and/or metachronous tumors. However, no case reports exist of germline BRCA1‐mutated synchronous and metachronous PACC. Case A 58‐year‐old man was diagnosed with synchronous and metachronous PACC at the age of 56 and underwent two surgeries. Ten months after the second surgery, the patient developed multiple liver metastases. Gemcitabine plus nab‐paclitaxel therapy was administered as first‐line chemotherapy. After seven cycles, computed tomography examination revealed progressive disease (PD). Therefore, modified FOLFIRINOX (mFFX) was administered as second‐ line chemotherapy. After 19 cycles of mFFX, comprehensive cancer genomic profiling (CGP) identified a BRCA1 pathogenic variant that was confirmed to be germline origin. Accordingly, we treated the patient with olaparib; however, he was diagnosed with PD after 4 months. He subsequently died 5 years and 9 months after the initial surgery, and 3 years and 10 months after chemotherapy. Based on the genetic data of the patients, his family members received genetic counseling followed by cascade testing. Consequently, the same gBRCA1 pathogenic variant was detected in the son and his surveillance for HBOC‐related cancers was initiated. Conclusion We diagnosed a 58‐year‐old man with a synchronous and metachronous PACC with germline BRCA1 pathogenic variant. Considering that PACC is likely to have BRCA1/2 mutations responsible for HBOC, we need to be aware of the possible presence of multifocal and/or metachronous tumors in patients with PACC. Additionally, patients with PACC should undergo genetic examinations, which would be beneficial in determining treatment strategies and health care for blood relatives.

associated of hereditary breast and ovarian cancer syndrome (HBOC).Hereditary cancers, including HBOC, are characterized by multifocal and/or metachronous tumors.Although PACC should be considered as part of the spectrum of BRCA1/2-related malignancies, reports do not exist of BRCA-mutated synchronous and metachronous PACC.We previously reported on this case as being the first instance of PACC that was found to be both synchronous and metachronous [6].Subsequent genetic testing revealed the presence of a germline BRCA1 mutation, proving that this was an HBOCassociated PACC.Herein, we highlight this PACC case as it suggests that aggressive genetic testing is required for this type of pancreatic cancer.

| Case
A 58-year-old man was previously diagnosed with PACC of the pancreatic tail at the age of 56 and underwent a distal pancreatectomy; two masses were identified in the caudal and body of the pancreas at Sapporo Medical University Hospital (Sapporo, Japan) in March 2017.Ten months after surgery, a residual recurrence was found in the pancreatic head.The patient subsequently underwent a total resection of the residual pancreas at the same hospital in April 2018.We have previously reported details of the clinical course of the cancer [6].Ten months after the second surgery, an abdominal computed tomography (CT) scan revealed three hypervascular masses in the liver.The hepatic tumor was diagnosed as a metastatic PACC based on the pathological analysis of a targeted hepatic tumor biopsy (Figure 1).Gemcitabine plus nab-paclitaxel (GnP) therapy (gemcitabine, 1000 mg/m 2 days 1, 8, 15; nab-paclitaxel, 125 mg/m 2 days 1, 8, 15; every 4 weeks) was administered as first-line chemotherapy.After seven cycles, CT examination revealed the tumor had changed into a hypovascular tumor but its size had increased.We judged this to be PD.A modified combination regimen of 5-fluorouracil, leucovorin, oxaliplatin, and irinotecan (modified FOLFIRINOX [mFFX]) therapy [5-fluorouracil, 2400 mg/m 2 days 1 and 2; leucovorin, 200 mg/ m 2 day 1; oxaliplatin, 85 mg/m 2 day 1; irinotecan, 150 mg/m 2 day 1; every 2 weeks] was administered as second-line chemotherapy.The best response was a partial response, resulting in a 78% reduction.After 19 cycles of mFFX, comprehensive cancer genomic profiling (CGP; FoundationOne CDx) was performed on the second set of surgical specimens in order to explore effective therapeutic options according to gene alterations.Pathogenic variants were found in BRCA1 (c.188T>A, L63*, allele frequencies: 60.64%) and SMAD4 (c.1239C>A, Y413*, allele frequencies: 16.01%).The patient showed a family history of HBOC-related

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cancers: For example, his aunt died in her 40s due to ovarian cancer.The same BRCA1 pathogenic variant was detected in the germline of the patient by a single-site sequencing; as a result, he was diagnosed with HBOC.After Japanese public health insurance covered treatment with olaparib, the patient was switched to this at a dose of 600 mg/day.After 4 months of treatment, the patient was judged to have PD.He was then treated with a reduced dose of mFFX (5-fluorouracil, 1800 mg/ m 2 days 1 and 2; leucovorin, 200 mg/m 2 day 1; oxaliplatin, 65 mg/ m 2 day 1; irinotecan, 120 mg/m 2 day 1; every 2 weeks), but the patient was judged to have PD after 5 months.Subsequently, he was treated with gemcitabine monotherapy (gemcitabine, 1000 mg/ m 2 days 1, 8, 15 every 4 weeks); a response was not observed.
The patient died 5 years and 9 months after his initial surgery, and 3 years and 8 months after the initiation of chemotherapy (Figure 2).His family members received genetic counseling and subsequent cascade genetic testing.The son and daughter underwent single-site sequencing and the same gBRCA1 pathogenic variant was detected in the patient's son, prompting the initiation of cancer surveillance thereafter (Figure 3).

| Discussion
PACC has genetic features that are distinct from PDAC.In one study, up to 45% of PACC cases had a deficiency of DNA damage repair pathway genes such as BRCA1/2 [2].Pathogenic variants in gBRCA1/2 are implicated in HBOC, which predisposes individuals to cancers such as those of the breast, ovary, pancreas, and prostate.The cumulative risk for developing pancreatic cancer by 70 years of the age is between 1% and 4% for carriers of gBRCA1/2 pathogenic variants [7].Pathogenic variants in DNA damage repair gene mutations, such as ATM, PALB2, and CHEK2, have also been shown to be associated with HBOC [8][9][10].Thus, PACC should be considered as part of the spectrum of HBOC-related malignancies with the potential for being both synchronous and metachronous cancers.However, no prior reports exist of synchronous and metachronous BRCA1/2-mutated PACC.To our knowledge, this case is the first such report.
The prognosis of postoperative recurrence or unresectable PACC remains poor, similar to that of PDAC [11].Accumulated evidence has shown that BRCA-mutated tumor cells are sensitive to platinum analog chemotherapeutics and poly ADP ribose polymerase (PARP) inhibitors [12].Specifically, the efficacies of platinum-based chemotherapy and PARP inhibitors for BRCAmutated pancreatic cancer, including PACC, have already been reported [13,14].In fact, the total duration of response in our case was approximately 14 months with platinum-based chemotherapy and PARP inhibitors, resulting in long-term survival.In addition to BRCA1/2 mutations, PACC has also been reported to have other druggable gene mutations, such as PALB2, ATM, BRAF, and JAK1 [15].Currently, few reports exist on the efficacy of genotype-matched therapy for PALB2, ATM, BRAF, and JAK1 mutations, with the exception of BRCA in PACC, with only case reports having achieved a CR with BRAF and MEK inhibitors for BRAF V600E [16].Although the efficacy of genotypematched therapy for PACC has to first be established in clinical trials, such treatments may be good candidates for a personalized approach to therapy based on the gene mutations in PACC.
Genetic counseling to assess a patient's genetic predisposition and to plan for future healthcare may be not beneficial for those with unresectable pancreatic cancer and a poor-prognosis.However, surveillance, risk-reducing surgery, and oncologic treatment for gBRCA1/2 carriers have been reported to be useful  In conclusion, we diagnosed a 58-year-old man with a synchronous and metachronous PACC that was subsequently found to have a gBRCA1 pathogenic variant.Considering PACC is likely to be positive for BRCA1/2 mutations responsible for HBOC, resectable cases should be closely followed up with the prospect that the PACC may be synchronous or metachronous cancer.In both resectable and unresectable cases, genetic tests should be performed to assist in healthcare, including cancer surveillance, for blood relatives.Furthermore, in unresectable cases, genetic tests may lead to assisting in the selection of chemotherapeutic regimens and may contribute to a prolonged prognosis.